The present invention relates to a process for the preparation of taxane derivatives of general formula: 
which are particularly advantageous intermediates for preparing taxol, Taxotere and their analogues which have notable antileukaemic and antitumour properties.
In the general formula (I),
Ar represents an aryl radical,
R represents the phenyl radical or a radical R5xe2x80x94Oxe2x80x94 in which R5 represents
a straight or branched alkyl radical containing 1 to 8 carbon atoms, an alkenyl radical containing 2 to 8 carbon atoms, an alkynyl radical containing 3 to 8 carbon atoms, a cycloalkyl radical containing 3 to 6 carbon atoms, a cycloalkenyl radical containing 4 to 6 carbon atoms or a bicycloalkyl radical containing 7 to 11 carbon atoms, these radicals optionally being substituted by one or a number of substituents chosen from the halogen atoms and the hydroxyl radical, alkoxy radical containing 1 to 4 carbon atoms, dialkylamino radical, each alkyl part of which contains 1 to 4 carbon atoms, piperidino radical, morpholino radical, 1-piperazinyl radical (optionally substituted in the 4-position by an alkyl radical containing 1 to 4 carbon atoms or by a phenylalkyl radical, the alkyl part of which contains 1 to 4 carbon atoms), cycloalkyl radical containing 3 to 6 carbon atoms, cycloalkenyl radical containing 4 to 6 carbon atoms, phenyl cyano radical, carboxyl radical or alkoxycarbonyl radical, the alkyl part of which contains 1 to 4 carbon atoms,
or a phenyl radical optionally substituted by one or a number of atoms or radicals chosen from the halogen atoms and the alkyl radicals containing 1 to 4 carbon atoms or the alkoxy radicals containing 1 to 4 carbon atoms,
a saturated or unsaturated nitrogen-containing heterocyclyl radical containing 4 to 6 members and optionally substituted by one or a number of alkyl radicals containing 1 to 4 carbon atoms, it being understood that the cycloalkyl, cycloalkenyl or bicycloalkyl radicals may optionally be substituted by one or a number of alkyl radicals containing 1 to 4 carbon atoms,
R1 and R2, which are identical or different, represent a hydrogen atom or an alkyl, phenylalkyl, phenyl, alkoxyphenyl or dialkoxyphenyl radical or else R1 and R2 form, together with the carbon atom to which they are bonded, a ring having from 4 to 7 members,
R3 represents an acetyl radical or a protective group of the hydroxyl functional group and
R4 represents a protective group of the hydroxyl functional group.
More particularly, Ar represents a phenyl or xcex1- or xcex2-naphthyl radical optionally substituted by one or a number of atoms or radicals, identical or different, chosen from the halogen atoms (fluorine, chlorine, bromine, iodine) and the alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxyl, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl, dialkylcarbamoyl, cyano, nitro and trifluoromethyl radicals, it being understood that the alkyl radicals and the alkyl portions of the other radicals contain 1 to 4 carbon atoms, that the alkenyl and alkynyl radicals contain 3 to 8 carbon atoms and that the aryl radicals are phenyl or xcex1- or xcex2-naphthyl radicals, or else Ar represents an aromatic heterocyclic radical having 5 members and containing one or a number of atoms, identical or different, chosen from the nitrogen, oxygen or sulphur atoms, optionally substituted by one or a number of substituents, identical or different, chosen from the halogen atoms (fluorine, chlorine, bromine, iodine) and the alkyl radicals containing 1 to 4 carbon atoms, aryl radicals containing 6 to 10 carbon atoms, alkoxy radical containing 1 to 4 carbon atoms, aryloxy radical containing 6 to 10 carbon atoms, amino radical, alkylamino radical containing 1 to 4 carbon atoms, dialkylamino radical, in which each alkyl part contains 1 to 4 carbon atoms, acylamino radical, the acyl part of which contains 1 to 4 carbon atoms, alkoxycarbonylamino radical containing 1 to 4 carbon atoms, acyl radical containing 1 to 4 carbon atoms, arylcarbonyl, the aryl part of which contains 6 to 10 carbon atoms, cyano radical, carboxyl radical, carbamoyl radical, alkylcarbamoyl radical, the alkyl part of which contains 1 to 4 carbon atoms, dialkylcarbamoyl radical, each alkyl part of which contains 1 to 4 carbon atoms, or alkoxycarbonyl radical, the alkoxy part of which contains 1 to 4 carbon atoms.
More particularly, Ar represents a phenyl, 2- or 3-thienyl or 2- or 3-furyl radical optionally substituted by one or a number of atoms or radicals, which are identical or different, chosen from the halogen atoms and the alkyl, alkoxy, amino, dialkylamino, acylamino, alkoxycarbonylamino and trifluoromethyl radicals.
More particularly still, Ar represents a phenyl radical optionally substituted by a chlorine or fluorine atom or by an alkyl (methyl), alkoxy (methoxy), dialkylamino (dimethylamino), acylamino (acetylamino) or alkoxycarbonylamino (t-butoxycarbonylamino) or 2- or 3-thienyl or 2- or 3-furyl radical.
More particularly, R. represents an acetyl radical or a protective group of the hydroxyl functional group chosen from the (2,2,2-trichloroethoxy)carbonyl, (2-trichloromethylisopropoxy)carbonyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl or triarylsilyl radicals in which the alkyl radicals contain 1 to 4 carbon atoms and the aryl radicals are, preferably, phenyl radicals and R4 represents a protective group of the hydroxyl functional group chosen from the (2,2,2-trichloroethoxy)carbonyl, (2-trichloromethylisopropoxy)carbonyl, benzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl or triarylsilyl radicals in which the alkyl radicals contain 1 to 4 carbon atoms and the aryl radicals are, preferably, phenyl radicals.
A description is given in International Application PCT WO 9209589 of the preparation of the products of general formula (I) by esterification of protected baccatin III or protected 10-deacetylbaccatin III of general formula: 
in which R3 and R4 are defined as above, by means of an acid of general formula: 
in which Ar, R1 and R2 are defined as above and Boc represents the t-butoxycarbonyl radical, and of their conversion to taxol, Taxotere or their derivatives of general formula: 
in which Ar is defined as above, R6 represents a hydrogen atom or the acetyl radical and R represents the phenyl radical or a radical R5xe2x80x94Oxe2x80x94 in which R5 is defined as above, by passing through the intermediacy of a product of general formula: 
in which R3 and R4 are defined as above.
According to the previously known processes, it was necessary, to obtain the products of general formula (IV), in which the absolute configuration of the side chain is necessary for the antitumoral activity, to use the acid of general formula (III) in which the carbon atoms in the 4- and 5-positions respectively have the S and R configurations.
It has now been found, and it is this which forms the subject of the present invention, that the products of general formula (I) can be obtained, with a stereoselectivity in the region of 100%, by esterification of protected baccatin III or protected 10-deacetylbaccatin III by means of an acid of general formula: 
in which Ar, R, R1 and R2 are defined as above and in which the carbon atoms in the 4- and 5-positions each have the S configuration, or of an activated derivative of this acid.
The process according to the invention makes it possible to stereoselectively obtain the product of general formula (I) from an acid of general formula (VI)i optionally mixed with an acid of general formula (III).
According to the present invention, the esterification of protected baccatin III or protected 10-deacetylbaccatin III by the acid of general formula (VI) is carried out in the presence of a condensation agent such as an imide, such as dicyclohexylcarbodiimide, or a reactive carbonate, such as di-2-pyridyl ketone, and of an activating agent such as an aminopyridine, such as 4-dimethylaminopyridine or 4-pyrrolidinopyridine, the reaction being carried out in an organic solvent chosen from ethers such as tatrahydrofuran, diisopropyl ether, methyl t-butyl ether or dioxane, ketones such as methyl isobutyl ketone, esters such as ethyl acetate, isopropyl acetate or n-butyl acetate, nitriles, aliphatic hydrocarbons such as pentane, hexane or heptane, halogenated aliphatic hydrocarbons such as dichloromethane or 1,2-dichloroethane and aromatic hydrocarbons such as benzene, toluene, xylenes, ethylbenzene, isopropylbenzene or chlorobenzene, at a temperature between 0 and 90xc2x0 C.
The esterification can also be carried out by using the acid of general formula (VI) in the anhydride form of general formula: 
in which Ar, R, R1 and R2 are defined as above, in the presence of an activating agent such an an aminopyridine, such as 4-dimethylaminopyridine or 4-pyrrolidinopyridine, the reaction being carried out in an organic solvent chosen from others such an tetrahydrofuran, diisopropyl ether, methyl t-butyl ether or dioxane, ketones such an methyl isobutyl ketone, esters such as ethyl acetate, isopropyl acetate or n-butyl acetate, nitriles such as aectonitrile, aliphatic hydrocarbons such as pentane, hexane or heptane, halogenated aliphatic hydrocarbons such as dichloromethane or 1,2-dichloroethane and aromatic hydrocarbons such as benzene, toluene, xylenes, ethylbenzene, isopropylbenzene or chlorobenzene, at a temperature between 0 and 90xc2x0 C.
The esterification can also be carried out by using the acid of general formula (VI) in the halide or mixed anhydride form of general formula: 
in which Ar, R, R1 and R2 are defined as above and X represents a halogen atom or an acyloxy or aroyloxy radical, optionally prepared in situ, in the presence of a base which is preferably a nitrogenous organic base such as a tertiary aliphatic amine, a pyridine or an aminopyridine, such as 4-dimethylaminopyridine or 4-pyrrolidinopyridine, the reaction being carried out in an inert organic solvent chosen from ethers such as tetrahydrofuran, diisopropyl ether, methyl t-butyl ether or dioxane, ketones such as methyl t-butyl ketone, esters such as ethyl acetate, isopropyl acetate or n-butyl acetate, nitriles such as acetonitrile, aliphatic hydrocarbons such as pentane, hexane or heptane, halogenated aliphatic hydrocarbons such as dichloromnethane or 1,2-dichloroethane and aromatic hydrocarbons such as benzene, toluene, xylenes, ethylbenzene, isopropylbenzene or chlorobenzene, at a temperature between 0 and 90xc2x0 C.
The acid of general formula (VI) can be obtained by saponification of the eater of general formula: 
in which Ar, R, R1 and R2 are defined as above and R7 represents an alkyl radical containing 1 to 4 carbon atoms optionally substituted by one or a number of phenyl radicals.
Generally, the saponification in carried out in aqueous medium, optionally in the presence of an aliphatic alcohol containing 1 to 4 carbon atoms (methanol, ethanol, isopropanol, t-butanol), in the presence of an inorganic bass chosen from hydroxides, carbonates or bicarbonates of alkali metals or alkaline-earth metals, at a temperature between 0 and 50xc2x0 C., preferably in the region of 20xc2x0 C.
The eater of general formula (IX) can be obtained by reacting an aldehyde or a ketone of general formula: 
in which R1 and R2 are defined as above, optionally in the form of a dialkyl acetal or of an enol alkyl ether, with an ester of general formula: 
in which Ar, R and R7 are defined as above, the reaction being carried out in an inert organic solvent in the presence of a strong inorganic acid, such as sulphuric acid, or a strong organic acid, such as p-toluenesulphonic acid, optionally in the pyridinium salt form, at a temperature between 0xc2x0 and the boiling temperature of the reaction mixture. Solvents which are particularly well suited are aromatic hydrocarbons such as toluene.
The ester of general formula (XI) can be obtained by reacting benzoyl chloride or a product of general formula R5xe2x80x94Oxe2x80x94COxe2x80x94Y, in which R5 is defined as above and Y represents a halogen atom or a radical xe2x80x94Oxe2x80x94R5 or xe2x80x94Oxe2x80x94COxe2x80x94R5, with an ester of general formula: 
in which Ar and R7 are defined as above, the reaction being carried out in an organic solvent such as an aliphatic ester, such as ethyl acetate, or a halogenated aliphatic hydrocarbon such as dichloromethane, optionally in the presence of an inorganic base such as sodium bicarbonate or an organic base such as triethylamine. Generally, the reaction is carried out at a temperature between 0 and 50xc2x0 C., preferably in the region of 20xc2x0 C.
The ester of general formula (XII) can be obtained according to the process described by E. Kamandi et al., Arch. Pharmaz., 308, 135-141 (1975).
The anhydride of general formula (VII) can be obtained by reacting a dehydrating agent such as dicyclohexylcarbodiimide with the acid of general formula (VI), the reaction being carried out in an organic solvent chosen from ethers such as tetrahydrofuran, diisopropyl ether, methyl t-butyl ether or dioxane, ketones such as methyl isobutyl ketone, esters such as ethyl acetate, isopropyl acetate or n-butyl acetate, nitriles such as acetonitrile, aliphatic hydrocarbons such as pentane, hexane or heptane, halogenated aliphatic hydrocarbons such as dichloromethane or 1,2-dichloroethane and aromatic hydrocarbons such as benzene, toluene, xylenes, ethylbenzene, isopropylbenzene or chlorobenzene, at a temperature between 0 and 30xc2x0 C.
The activated acid of general formula (VIII) can be obtained by reacting a sulphuryl halide, preferably the chloride, or a product of general formula:
R8xe2x80x94COxe2x80x94Zxe2x80x83xe2x80x83(XIII)
in which R8 represents an alkyl radical containing 1 to 4 carbon atoms or a phenyl radical optionally substituted by 1 to 5 atoms or radicals, which are identical or different, chosen from the halogen atoms and the nitro, methyl or methoxy radicals and Z represents a halogen atom, preferably a chlorine atom, with an acid of general formula (VI), the reaction being carried out in a suitable organic solvent, such as tetrahydrofuran, in the presence of an organic base such as a tertiary amine, such as triethylamine, at a temperature between 0 and 30xc2x0 C.
The acid of general formula (VI) can also be obtained by oxidation of a product of general formula: 
in which Ar, R, R1 and R2 are defined as above.
Generally, the oxidation is carried out by means of an alkali metal periodate (sodium periodate), in the presence of a catalytic amount of a ruthenium salt (RuCl3) and of sodium bicarbonate, the reaction being carried out in aqueous/organic medium such as, for example, an acetonitrile/carbon tetrachloride/water mixture. Generally, the reaction is carried out at a temperature in the region of 20xc2x0 C.
The product of general formula (XIV) can be obtained by reacting an aldehyde or a ketone of general formula (X), optionally in the form of a dialkyl acetal or of an enol eater, with a product of general formula: 
in which Ar and R are defined as above, the reaction being carried out in an inert organic solvent in the presence of a strong inorganic acid, such as sulphuric acid, or a strong organic acid, such as p-toluenesulphonic acid, optionally in the pyridinium salt form, at a temperature between 0xc2x0 C. and the boiling temperature of the reaction mixture. Solvents which are particularly well suited are aromatic hydrocarbons.
The product of general formula (XV) can be obtained under the conditions described in EP-A-0,530,385.
The ester of general formula (IX), in which Ar and R7 are defined as above, R1 represents a hydrogen atom and R2 represents a phenyl, alkoxyphenyl or dialkoxyphenyl radical, can also be obtained by cyclization of a product of general formula: 
in which Ar, R and R7 are defined as above and Ph represents a phenyl, alkoxyphenyl or dialkoxyphenyl radical, the reaction preferably being carried out in anhydrous medium, in an organic solvent chosen from ethers, esters, ketones, nitriles, optionally halogenated aliphatic hydrocarbons and optionally halogenated aromatic hydrocarbons in the presence of an oxidizing agent such as dichlorodicyanobenzoquinone at a temperature between 0xc2x0 C. and the boiling temperature of the reaction mixture. The reaction is preferably carried out in an halogenatedaliphatic hydrocarbon, such as dichloromethane, or acetonitrile at a temperature in the region of 20xc2x0 C.
The cyclization leads to the formation of a mixture of 2R and 2S epimers of the product of general formula (IX) which can be separated according to the usual methods. It is particularly advantageous to preferentially obtain the 2R epimer in order to prepare taxol, Taxotere or their derivatives from a product of general formula (I).
The invention also relates to the acids of general formula (VI), optionally in the salt, ester, anhydride, mixed anhydride or halide form.
The taxane derivatives of general formula (I) obtained by the use of the process according to the invention can be converted to taxol, Taxotere or their analogues according to the processes described in International Application PCT WO 9209589, when R1 and R2 each represent an alkyl or phenylalkyl radical by passing through the intermediacy of the product of general formula (V) or else by treatment in acid medium (hydrochloric acid, sulphuric acid, acetic acid, methanesulphonic acid, trifluoromethanesulphonic acid, p-toluenesulphonic acid), the reaction being carried out in an organic solvent (alcohol, ether, ester, aliphatic hydrocarbon, halogenated aliphatic hydrocarbon, aromatic hydrocarbon, nitrile) at a temperature between xe2x88x9210 and 60xc2x0 C, or, when R1 represents a hydrogen atom and R2 represents a phenyl, alkoxyphenyl or dialkoxyphenyl radical, by passing through the intermediacy of a product of general formula 
in which Ar, R and Ph are defined as above and Rxe2x80x2 represents a hydrogen atom or the acetyl radical, after replacement of the protective groups R4 and optionally R3 by hydrogen atoms according to known methods.